This proposal offers an exciting interdisciplinary approach to fundamental problems of cochlear function and dysfunction. It is based on current theories of regulatory mechanisms governing cell physiology and on novel molecular genetic approaches to the identification of genes and gene products. The unifying theme of cochlear homeostatic mechanisms is addressed in five projects representing molecular biology and genetics (Projects I, II and III) and molecular cell biology and biochemistry (Projects IV and V). The proposal combines diversified and powerful steps to investigate the normal system (Project V), the system under stress (Projects III and IV) and the genetically altered system (Projects I and II). Projects IV and V propose hypothesis-driven investigations related to the role of calcium in cochlear mechanisms (Project V) and to the function of heat shock proteins in cochlear trauma (Project IV). These studies are paired with the exciting new methods that molecular biology and genetics provide. Projects I and II propose positional cloning of mouse deafness mutants ames waltzer and pirouette, respectively. Project III uses auditory-specific trauma to identify genes by differential display. The interdisciplinary approach strengthened additionally by the resource available through the Kresge Hearing Research Institute. The Histology Core is responsible for providing morphological and histochemical assessments. Likewise, the Physiology Core will provide electrophysiological characterization of mutations, trauma and normal function. These cores are essential components of the Program Project, providing anatomical and functional feedback critical to the hypotheses and specific aims of other projects. In summary, the present proposal represents a broadly based yet focused approach to the study of molecular mechanisms in cochlear homeostasis. It is particularly powerful through its interdisciplinary nature and the ability to place molecular genetics and molecular biology into a systems context. As disease or dysfunction are an aberration of homeostatic mechanisms, the current studies will yield major fundamental information and enable us to design novel ways to prevent trauma to the inner ear or to accelerate recovery from such trauma.